Alkali metal and alkaline-earth metal salts of omeprazole and enantiomers thereof are well known as gastric secretion inhibitors and antiulcer agents. Among these, the magnesium salt of the (S) enantiomer of omeprazole, or esomeprazole or 5-methoxy-2-[(S)-[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, is the first proton pump inhibitor (PPI) developed and sold in pure enantiomer form. The company Astra Zeneca thus markets this compound in trihydrate form, under the trade name Inexium®. Other companies have developed a magnesium salt of esomeprazole in dihydrate form.
Processes for preparing these compounds are described in the literature.
Thus, patent application WO 2004/002982 describes the separation of racemic omeprazole into its pure enantiomers by formation of diastereomeric salts from the sodium salt of racemic omeprazole placed in contact with the coordinating agent diethyl-D-tartrate/Ti (iso-Pr)4 in acetone and complexation using L-mandelic acid. Selective crystallization of the diastereomer comprising esomeprazole followed by a basic hydrolysis gives the magnesium salt of esomeprazole trihydrate in 99% ee. Formation of the corresponding dihydrate is obtained by controlled drying.
Patent application WO 2004/046134 describes the preparation of the magnesium salt of esomeprazole trihydrate in crystalline form II from the amorphous form of the same salt, which is dissolved in methanol to form a solution. After filtration, removal of the solvent and precipitation from water, a solid is obtained, which is washed with a mixture of water and acetone and then dried.
Patent application WO 2004/089935 also describes the preparation of a novel crystalline form of the magnesium salt of esomeprazole trihydrate, known as H1, characterized by its powder X-ray diffraction diagram.
Patent application WO 2007/031845 also describes the preparation of a magnesium salt of esomeprazole trihydrate, in two polymorphic crystalline forms G1 and G2, by reacting the sodium salt of esomeprazole with aqueous magnesium sulfate solution.
For its part, patent application WO 98/54171 describes the formation of the magnesium salt of the omeprazole trihydrate enantiomers, and also of the dihydrate in the crystalline forms A and B. It is indicated that the trihydrate of the magnesium salt of esomeprazole may be prepared by hydration of a magnesium salt of esomeprazole of crystalline form I, obtained as described in document WO 96/01623, i.e. from esomeprazole and magnesium methoxide in acetone. As a variant, the trihydrate may be prepared by reacting the potassium salt of esomeprazole with magnesium sulfate in water. To obtain the dihydrate form A, magnesium sulfate is dissolved in methanol, and a mixture of water and acetone is then added to the reaction product.
Document WO 2008/102145 teaches an alternative process for the crystallization of the dihydrate form A, which is supposed to overcome the insufficiencies of the process described in WO 98/54171, which is said to lead to an unstable compound, which is liable to become converted on drying into trihydrate or into an amorphous form. Examples to 9 of WO 2008/102 145 thus disclose a process comprising steps of: (a) reacting the potassium salt of esomeprazole with a magnesium salt (such as magnesium chloride hexahydrate) in alcoholic medium (especially in methanol), (b) filtration of the insoluble matter, (c) addition of a water/acetone mixture to the insoluble matter, (d) filtration, washing with ethyl acetate and drying.
Such a process requires the use of several organic solvents, some of which, such as methanol, may pose toxicology problems, and which must in any case be removed during the process in order to obtain a product that is as pure as possible.
More recently, patent application FR 2 920 428 has proposed a process described as leading to the magnesium salt of esomeprazole tetrahydrate. This process, illustrated in Example 10 of said application, consists in dissolving in aqueous potassium hydroxide solution a potassium salt of esomeprazole, and then in reacting this salt with magnesium chloride dissolved in a mixture of water and acetone. It is indicated that the tetrahydrate is obtained in an unoptimized yield of 35%. The inventors however realized, after numerous attempts, that this process was not reproducible and led almost every time to the trihydrate of the magnesium salt of esomeprazole.
The general description of said document suggests other processes for synthesizing the tetrahydrate by cation exchange starting with the potassium salt, without further details. Now, the teaching of the prior art mentioned previously shows that the reaction of a magnesium salt with the same potassium salt of esomeprazole, as a function especially of the solvents used, leads to a diversity of crystalline and/or hydrate forms. In addition, the need to perform the reaction in the presence of potassium hydroxide induces pollution of the product obtained with residual potassium ions, which affects the purity of this product.
It would thus be desirable to have available a novel process for preparing a magnesium salt of an enantiomer of omeprazole tetrahydrate that is economical, easy to perform, and that leads reproducibly and in a yield of at least 50% to a compound whose purity is acceptable for pharmaceutical use, especially with a low content of potassium.